title: PAK4 is required for regulation of the cell-cycle regulatory protein p21, and for control of cell-cycle progression.
abstract: The serine/threonine kinase PAK4 regulates cytoskeletal architecture, and controls cell proliferation and survival. In most adult tissues PAK4 is expressed at low levels, but overexpression of PAK4 is associated with uncontrolled proliferation, inappropriate cell survival, and oncogenic transformation. Here we have studied for the first time, the role for PAK4 in the cell cycle. We found that PAK4 levels peak dramatically but transiently in the early part of G1 phase. Deletion of Pak4 was also associated with an increase in p21 levels, and PAK4 was required for normal p21 degradation. In serum-starved cells, the absence of PAK4 led to a reduction in the amount of cells in G1, and an increase in the amount of cells in G2/M phase. We propose that the transient increase in PAK4 levels at early G1 reduces p21 levels, thereby abrogating the activity of CDK4/CDK6 kinases, and allowing cells to proceed with the cell cycle in a precisely coordinated way.
authors.affiliation: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey Piscataway, New Jersey 08854, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Nekrasova
authors.forename: Audrey
authors.initials: A
authors.lastname: Minden
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000502:physiology; D016193:G1 Phase; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D055550:Protein Stability; D014158:Transcription, Genetic; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C486708:Pak7 protein, mouse; C492065:Pak4 protein, mouse; D054462:p21-Activated Kinases; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D020741:rho GTP-Binding Proteins